Background:  Etravine (TMC125) is a next-generation NNRTI that has demonstrated significant antiviral activity in 2 large phase III trials, DUET-1 and 2, conducted in HIV-infected adults with evidence of NNRTI resistance. Pediatric dosing of TMC125 has not been established. The objective of this study is to determine the weight-based dose of TMC125 that will achieve exposures in children comparable to those in adults.

Methods:  HIV-1-infected children between 6 and ≤17 years of age with at least 2 consecutive viral loads <50 copies/mL on a lopinavir/ritonavir (LPV/r) -containing regimen were enrolled. TMC125 4 mg/kg twice daily was added for 7 days followed by a morning dose, and 12-hour pharmacokinetics assessment on day 8. Both 25- and 100-mg tablets were used. TMC125 pharmacokinetics was assessed using non-compartmental analysis; C_min and AUC_12h were compared to parameters previously established in adults administered 200 mg twice daily on a LPV/r-containing regimen. Safety and tolerability were assessed throughout the study until 30 days post-dosing.

Results:  We enrolled 17 children; pharmacokinetic assays were available for 16, of whom 10 were between the ages of 6 and <12, and 6 between the ages of ≥12 and ≤17. The mean (SD) C_max and C_min in 16 children were 555.2 (514.6) ng/mL and 233.2 (237.9) ng/mL, respectively. Mean (SD) AUC_12h was evaluable in 15 children and was 4788 (4459) ng·h/mL. Relative to adults, the least square means ratio (90% confidence interval) for C_min and AUC_12h was 1.08 (0.69 to 1.69) and 1.11 (0.76- to .62), respectively. Intersubject pharmacokinetics variability was greater in children than adults, primarily as a result of 1 outlier. The range of exposures observed in children with the outlier removed was similar to that observed in adults. Exposure was not associated with age or weight. No serious adverse events occurred; 12 children reported at least 1 adverse event, mostly grade 1 or 2; 2 children developed a rash (grade 1 and 2, respectively), both on day 8 and resolving after 5 to 6 days; the AUC_12h in these children were 7408 and 1826 ng·h/mL, respectively.

Conclusions:  In children 6 to 17 years old (inclusive), TMC125, 4 mg/kg twice daily, provides comparable exposure to the adult dose of TMC125 (200 mg twice daily) and was generally safe and well tolerated. Rash did not appear to be related to AUC_12h in this small study. Given the concern for under dosing antiretrovirals in children in general, the pharmacokinetics, short-term safety and tolerability of TMC125 administered at 5.2 mg/kg twice daily will be further investigated.